Bakkenolide G, a natural PAF-receptor antagonist.
Because platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) participates in many physiopathological responses, including inflammatory reaction, endotoxic shock, allergic diseases and platelet aggregation, PAF-receptor antagonists are important in the treatment of these diseases. A biologically active compound, bakkenolide G, extracted from the plant Petasites formosanus selectively and concentration-dependently inhibited PAF-induced platelet aggregation and ATP release. The IC50 of bakkenolide G for PAF (2 ng mL(-1))-induced platelet aggregation was 5.6 +/- 0.9 microM. Bakkenolide G also concentration-dependently inhibited PAF-induced intracellular signal transductions, including thromboxane B2 formation, and increased intra-cellular calcium concentration and phosphoinositide breakdown without affecting those caused by thrombin (0.1 units mL(-1)), collagen (10 microg mL(-1)), arachidonic acid (100 microM) and U46619 (1 microM). Bakkenolide G shifted the concentration-response curves of PAF-induced platelet aggregation parallel to the right; the Schild plot slope and the pA2 value were 1.31 +/- 0.31 and 6.21 +/- 0.75, respectively. Moreover, bakkenolide G concentration-dependently competed with [3H]PAF binding to platelets, with an IC50 value of 2.5 +/- 0.4 microM. These data strongly indicate that bakkenolide G is a specific PAF-receptor antagonist as an antiplatelet aggregatory agent.
Liao
C H
CH
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei.
Ko
F N
FN
Wu
T S
TS
Teng
C M
CM
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D015394:Molecular Structure; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D011817:Rabbits; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012717:Sesquiterpenes; D013141:Spiro Compounds / Q000494:pharmacology*; D013917:Thrombin / Q000494:pharmacology; D013929:Thromboxane B2 / Q000096:biosynthesis
D007295:Inositol Phosphates; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012717:Sesquiterpenes; D013141:Spiro Compounds; C110814:bakkenolide G; C039351:platelet activating factor receptor; D016718:Arachidonic Acid; D013929:Thromboxane B2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000255:Adenosine Triphosphate; D003094:Collagen; D013917:Thrombin; D015107:4-Butyrolactone; D002118:Calcium; D004121:Dimethyl Sulfoxide